Among American men, advanced prostate cancer (CaP) is presently the most frequently diagnosed cancer and is the second leading causes of cancer-related deaths. In 2009, an estimated 192,280 American men will be diagnosed with CaP and 27,360 will die of the disease. While early stage disease is frequently curable with surgery or radiation therapy, approximately ⅓ of patients clinically present with locally advanced or metastatic disease that is associated with a poor prognosis. Therapeutic androgen suppression through surgical or medical castration still remains the most effective therapy for advanced CaP since its inception in 1941 by Charles Huggins (Huggins and Hodges 1941). Androgen suppression consistently induces tumour regression in over 80% of patients with advanced disease due to the exquisite dependence of CaP cells on the androgen signaling axis for their growth and survival (Isaacs et al. 1997). Furthermore, Androgen Receptor (AR) expression is maintained throughout prostate cancer progression, and the majority of androgen independent or hormone refractory prostate cancers express AR (Heinlein and Chang 2004). However, despite initial success in achieving significant and tangible clinical responses, the duration of progression-free survival remains transient (˜1-3 years) and progression to lethal castration-resistant disease (also frequently referred to as androgen independent or hormone refractory disease) is essentially universal (Bruchovsky et al. 1988; Goldenberg et al. 1988; Bruchovsky et al. 1989). Thus, the current standard of care for patients with Castration-Resistant Prostate Cancer (CRPC) remains only palliative, with chemotherapy—eg. docetaxel (Petrylak et al. 2004; Tannock et al. 2004) inducing only marginal survival benefits at a cost of, at times, significant morbidity.
Semaphorins are a large family of highly conserved secreted or cell surface signaling proteins that were originally identified as mediators of cell migration and axon guidance in the developing nervous system (Tamagnone and Comoglio 2000; Kruger et al. 2005). While semaphorins have been best characterized in the nervous system, they are known to be expressed in other tissues. Semaphorins have been implicated in a variety of dynamic physiological processes including angiogenesis, tissue morphogenesis, and immunity (Kolodkin et al. 1993; Kruger et al. 2005). Semaphorins regulate numerous biological responses including cell proliferation, adhesion, migration and apoptosis through interaction of semaphorins with their cognate receptors, plexins. Plexins are single pass transmembrane receptors that have highly conserved intracellular domains that have intrinsic GAP (GTPase-activating protein) activity towards R-Ras12 (Negishi et al. 2005). Nine vertebrate plexins have been identified, grouped into four subfamilies (Plexin A to D) based on computational phylogenetic analyses. Semaphorins and plexins both express a conserved 500 amino acid extracellular motif called the SEMA domain that is thought to be involved in protein-protein interactions. Membrane-associated semaphorins bind directly to plexins whereas secreted semaphorins, often have an additional binding component (either neuropilins 1 or 2 (Npn-1 or Npn-2)) as co-receptors. Plexins are thought to regulate the actin cytoskeleton by controlling the activity of the small GTPases, Rnd1, R-Ras, Rac and Rho12. When plexins bind to semaphorin they are thought to also interact with and activate the receptor tyrosine kinases, Her2/neu (ErbB2), and hepatocyte growth factor/scatter factor receptor (c-Met) (Giordano et al. 2002; Swiercz et al. 2004; Swiercz et al. 2008).
SEMA3C is a member of the class 3 semaphorins, which are a subfamily of secreted semaphorins (Tamagnone and Comoglio 2000; Verras et al. 2007). SEMA3C may mediate opposing effects depending on the target cell type. For example, SEMA3C provides chemorepulsive axon guidance to sympathetic neurons whereas SEMA3C provides chemoattractive guidance for GABAnergic neurons. The specificity of semaphorin signals in each cell type depends on the combination of neuropilin/plexin present and their association with accessory receptors. SEMA3C has been shown to bind to receptor complexes comprised of Plexin A1, A2, or B1 in association with either Npn-1 or Npn-210. Plexins can actively influence their binding affinity (and possibly selectivity) for the different subsets of secreted semaphorins. For example, the binding of SEMA3C to neuropilins seems to be inhibited by the co-expression of plexin A1, whereas it is increased in the presence of plexin A2 or B1.
Herman and Meadows (2007) suggest an association between SEMA3C expression and increased invasion and adhesion in PC-3 AR negative cancer cells. However, AR negative prostate cancers represent a small minority of late stage androgen independent prostate cancers (Heinlein and Chang 2004).